Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. Epidemiological studies suggest that alcohol consumption also modulates the risk for the development of type 2 diabetes, the most common metabolic disease among older North Americans, with light alcohol consumption decreasing risk and chronic heavy alcohol consumption increasing risk in a J-shaped curve. Chronic, heavy ethanol exposure results in the development of glucose intolerance and insulin resistance. Since insulin resistance is commonly associated with the progression of liver disease in individuals with metabolic syndrome, as well as the development of type 2 diabetes, we hypothesize that ethanol-induced insulin resistance also contributes to the progression of alcoholic liver disease. In the past granting period, we have made significant progress in understanding the molecular and cellular mechanisms by which chronic, heavy ethanol feeding results in the development of insulin resistance, both in relation to glucose and lipid homeostasis. We have identified adipose tissue as a specific target of ethanol action. While the role of adipose tissue in the regulation of energy stores has long been appreciated, there is a growing understanding for the critical role of adipose tissue in regulating metabolic homeostasis, including the ability to modulate insulin sensitivity in skeletal muscle and liver, contribute to the regulation of inflammatory responses, as well as regulating appetitive behaviors. Given these essential roles for adipose tissue, the long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic and regulatory activity of adipose tissue and.determine the impact of these chronic ethanol-induced changes in adipose tissue in mediating the pathophysiological effects of chronic ethanol. During the extension of this research plan, we propose to investigate the hypothesis that changes in the metabolic and regulatory activity of adipose tissue in response to chronic ethanol consumption are important contributors to spreading of tissue injury between organs, particularly to the liver and kidney. We will investigate the following specific aims: Specific Aim 1: Determine the molecular and cellular mechanisms for activation of complement in adipose tissue after chronic ethanol exposure; Specific Aim 2: Determine if blockade of the Clq pathway and complement activation can prevent or reverse adipose tissue inflammation and insulin resistance after chronic ethanol; Specific Aim 3: Understand the broader impact on the ethanol on the adipocyte secretome and the influence of the adipose secretome in the spread of tissue injury after chronic ethanol feeding. Understanding the mechanisms by which chronic ethanol disrupts the metabolic and regulatory activity of adipose tissue, and the impact of these changes on hepatic function, will likely lead to the development of novel therapeutic strategies to prevent and/or reverse alcoholic liver disease. RELEVANCE (See instructions): Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. The long-term goals of this research project are to investigate the mechanisms by which ethanol disrupts the metabolic activity of adipose tissue and determine the impact of these chronic ethanol-induced changes in adipose tissue in the development of alcoholic liver disease.